HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial.
HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial.
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DOI：
10.1001/jamaoncol.2017.0184
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发表时间：
2017-08-01
期刊：
影响因子：
28.4
通讯作者：
Gottschalk S
中科院分区：
文献类型：
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作者：
Ahmed N;Brawley V;Hegde M;Bielamowicz K;Kalra M;Landi D;Robertson C;Gray TL;Diouf O;Wakefield A;Ghazi A;Gerken C;Yi Z;Ashoori A;Wu MF;Liu H;Rooney C;Dotti G;Gee A;Su J;Kew Y;Baskin D;Zhang YJ;New P;Grilley B;Stojakovic M;Hicks J;Powell SZ;Brenner MK;Heslop HE;Grossman R;Wels WS;Gottschalk S
胶质母细胞瘤是一种无法治愈的肿瘤，患者的治疗选择有限。确定全身给予HER 2特异性嵌合抗原受体（CAR）修饰的病毒特异性T细胞（VST）是否安全，以及这些细胞是否具有抗胶质母细胞瘤活性。在贝勒医学院、休斯顿卫理公会医院和德克萨斯州儿童医院进行的这项开放标签1期剂量递增研究中，2011年7月25日至2014年4月21日期间招募了进展性HER 2阳性胶质母细胞瘤患者。随访时间为10周至29个月（中位数，8个月）。用对巨细胞病毒、EB病毒或腺病毒具有特异性的自体VST进行单药治疗，并且经遗传修饰以表达具有CD 28信号传导内域的HER 2-汽车（HER 2-CAR VST）。主要终点是可行性和安全性。关键的次要终点是T细胞持久性及其抗胶质母细胞瘤活性。共有17例患者（8名女性和9名男性; 10名患者≥ 18岁[中位年龄，60岁;范围，30-69岁]和7名患者<18岁[中位年龄，14岁;范围，10-17岁]），接受1次或多次自体HER 2-CAR VST输注（1 × 106/m2至1 × 108/m2），既往无淋巴细胞耗竭。输注耐受性良好，无剂量限制性毒性作用。通过定量实时聚合酶链反应在输注后长达12个月的外周血中检测HER 2-CAR VST。在16例可评估患者（9例成人和7例儿童）中，1例部分缓解超过9个月，7例疾病稳定8周至29个月，8例在T细胞输注后进展。3名病情稳定的患者在24至29个月的随访期间存活，无任何进展证据。对于整个研究队列，从首次T细胞输注开始的中位总生存期为11.1个月（95% CI，4.1-27.2个月），从诊断开始的中位总生存期为24.5个月（95% CI，17.2-34.6个月）。输注自体HER 2-CAR VST是安全的，可能与进展性胶质母细胞瘤患者的临床获益相关。在2b期研究中，HER 2-CAR VST作为单一药物或与其他免疫调节方法联合用于胶质母细胞瘤的进一步评价是必要的。
Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)–modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children’s Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months). Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.ζ-signaling endodomain (HER2-CAR VSTs). Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity. A total of 17 patients (8 females and 9 males; 10 patients ≥ 18 years [median age, 60 years; range, 30–69 years] and 7 patients <18 years [median age, 14 years; range, 10–17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1 × 106/m2 to 1 × 108/m2) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1–27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2–34.6 months) from diagnosis. Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma. Further evaluation of HER2-CAR VSTs in a phase 2b study is warranted as a single agent or in combination with other immunomodulatory approaches for glioblastoma.
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病毒特异性的T细胞设计为共表达肿瘤特异性受体：神经母细胞瘤个体中的持久性和抗肿瘤活性。
影响因子：
82.9
作者：
通讯作者：
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影响因子：
20.3
作者：
Leen, Ann M.;Bollard, Catherine M.;Heslop, Helen E.
通讯作者：
Heslop, Helen E.
影响因子：
45.3
作者：
Ahmed, Nabil;Brawley, Vita S.;Gottschalk, Stephen
通讯作者：
Gottschalk, Stephen
DOI：
10.1158/1078-0432.ccr-09-1322
发表时间：
2010-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ahmed N;Salsman VS;Kew Y;Shaffer D;Powell S;Zhang YJ;Grossman RG;Heslop HE;Gottschalk S
通讯作者：
Gottschalk S
DOI：
10.1056/nejmoa1407222
发表时间：
2014-10-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maude SL;Frey N;Shaw PA;Aplenc R;Barrett DM;Bunin NJ;Chew A;Gonzalez VE;Zheng Z;Lacey SF;Mahnke YD;Melenhorst JJ;Rheingold SR;Shen A;Teachey DT;Levine BL;June CH;Porter DL;Grupp SA
通讯作者：
Grupp SA